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Hyperglycemia Increases Interstitial Cells of Cajal via MAPK1 and MAPK3
Signaling to ETV1 and KIT, Leading to Rapid Gastric Emptying.
Authors Hayashi Y, Toyomasu Y, Saravanaperumal SA, Bardsley MR, Smestad JA, Lorincz A,
Eisenman ST, Cipriani G, Nelson Holte MH, Al Khazal FJ, Syed SA, Gajdos GB, Choi
KM, Stoltz GJ, Miller KE, Kendrick ML, Rubin BP, Gibbons SJ, Bharucha AE, Linden
DR, Maher LJ, Farrugia G, Ordog T
Submitted By Gianrico Farrugia on 5/1/2017
Status Published
Journal Gastroenterology
Year 2017
Date Published 4/1/2017
Volume : Pages Not Specified : Not Specified
PubMed Reference 28438610
Abstract Depletion of interstitial cells of Cajal (ICCs) is common in diabetic
gastroparesis. However, in approximately 20% of patients with diabetes, gastric
emptying (GE) is accelerated. GE is also faster in obese individuals, and is
associated with increased blood levels of glucose in patients with type 2
diabetes. To understand the fate of ICCs in hyperinsulinemic, hyperglycemic
states characterized by rapid GE, we studied mice with mutation of the leptin
receptor (Lepr(db/db)), which in our colony had accelerated GE. We also
investigated hyperglycemia-induced signaling in the ICC lineage and ICC
dependence on glucose oxidative metabolism in mice with disruption of the
succinate dehydrogenase complex, subunit C gene (Sdhc)., Mice were given breath
tests to analyze GE of solids. ICCs were studied by flow cytometry,
intracellular electrophysiology, isometric contractility measurement, reverse
transcription PCR, immunoblot, immunohistochemistry, ELISAs, and metabolite
assays; cells and tissues were manipulated pharmacologically and by RNA
interference. Viable cell counts, proliferation, and apoptosis were determined
by methyltetrazolium, Ki-67, proliferating cell nuclear antigen,
bromodeoxyuridine, and caspase-Glo 3/7 assays. Sdhc was disrupted in 2 different
strains of mice via cre recombinase., In obese, hyperglycemic, hyperinsulinemic
female Lepr(db/db) mice, GE was accelerated and gastric ICC and phasic
cholinergic responses were increased. Female Kit(K641E/+) mice, which have
genetically induced hyperplasia of ICCs, also had accelerated GE. In isolated
cells of the ICC lineage and gastric organotypic cultures, hyperglycemia
stimulated proliferation by mitogen-activated protein kinase 1 (MAPK1)- and
MAPK3-dependent stabilization of ets variant 1 (ETV1)-a master transcription
factor for ICCs-and consequent upregulation of KIT proto-oncogene receptor
tyrosine kinase (KIT). Opposite changes occurred in mice with disruption of
Sdhc., Hyperglycemia increases ICCs via oxidative metabolism-dependent, MAPK1-
and MAKP3-mediated stabilization of ETV1 and increased expression of KIT,
causing rapid gastric emptying. Increases in ICCs might contribute to the
acceleration in GE observed in some patients with diabetes.